DNA Methyltransferase 1 Is Indispensable for Development of the Hippocampal Dentate Gyrus
DNA Methyltransferase 1 Is Indispensable for Development of the Hippocampal Dentate Gyrus
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DOI：
10.1523/jneurosci.0512-16.2016
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发表时间：
2016-06-01
影响因子：
5.3
通讯作者：
Nakashima, Kinichi
中科院分区：
文献类型：
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作者：
Noguchi, Hirofumi;Murao, Naoya;Nakashima, Kinichi
哺乳动物大脑中海马齿状回（DG）的发育是在胚胎晚期和出生后阶段通过多个过程实现的，每个发育步骤都严格受细胞外线索和细胞内机制的控制。在这里，我们表明，维持DNA甲基转移酶1（Dnmt 1）是至关重要的发展的DG在小鼠。在DG发育的开始，神经干细胞（NSCs）中Dnmt 1的缺失导致DG中颗粒细胞层的较小尺寸。缺乏Dnmt 1的神经干细胞未能建立适当的放射状突起或迁移到颗粒下区，导致DG分子层中神经元的异常产生和颗粒细胞层中整合神经元的减少。有趣的是，NSC中Dnmt 1的产前缺失不仅影响DG的发育进程，而且影响NSC维持到成年期的特性：Dnmt 1缺陷的NSC表现出受损的神经发生能力和增殖。我们还发现，Dnmt 1缺陷在神经干细胞中的发展DG中的Reelin信号成分的表达降低，并增加了细胞周期抑制剂p21和p57在成年DG中的表达。总之，这些发现使我们提出，Dnmt 1作为一个关键的调节器，以确保DG的适当发展，以及适当的状态，神经干细胞维持到成年，通过调节细胞外信号和细胞内机制。
Development of the hippocampal dentate gyrus (DG) in the mammalian brain is achieved through multiple processes during late embryonic and postnatal stages, with each developmental step being strictly governed by extracellular cues and intracellular mechanisms. Here, we show that the maintenance DNA methyltransferase 1 (Dnmt1) is critical for development of the DG in the mouse. Deletion of Dnmt1 in neural stem cells (NSCs) at the beginning of DG development led to a smaller size of the granule cell layer in the DG. NSCs lacking Dnmt1 failed to establish proper radial processes or to migrate into the subgranular zone, resulting in aberrant neuronal production in the molecular layer of the DG and a reduction of integrated neurons in the granule cell layer. Interestingly, prenatal deletion of Dnmt1 in NSCs affected not only the developmental progression of the DG but also the properties of NSCs maintained into adulthood: Dnmt1-deficient NSCs displayed impaired neurogenic ability and proliferation. We also found that Dnmt1 deficiency in NSCs decreased the expression of Reelin signaling components in the developing DG and increased that of the cell cycle inhibitors p21 and p57 in the adult DG. Together, these findings led us to propose that Dnmt1 functions as a key regulator to ensure the proper development of the DG, as well as the proper status of NSCs maintained into adulthood, by modulating extracellular signaling and intracellular mechanisms.